Cadmium (Cd) is a nephrotoxic metal which is used extensively in the electroplating industry and in the manufacture of pigments, plastics, and batteries. Human toxicity has resulted from occupational exposures to Cd and from environmental contamination with industrial waste. Prolonged exposure to inorganic Cd results in a renal tubular nephropathy which is similar in character to the Fabconi Syndrome. An abundance of evidence suggests that the nephrotoxicity which accompanies prolonged exposure to inorganic Cd may not be due solely to the direct renal accumulation of inorganic Cd, but to the formation of an extracellular nephrotoxic complex between Cd and the endogenous metal binding protein, metallothionein (Cd-MT). Despite the probable importance of Cd-MT in the development of Cd-induced nephrotoxicity, very little is known about the renal handling of Cd-MT or its effects on renal function. Based on a rationale that understanding these phenomena will promote a better understanding of the toxicology ofCd, the proposed study will seek to elucidate mechanisms involved in the renal handling of extracellular Cd-MT and the early effects of extracellular Cd-MT on renal transport and metabolism. It will also seek to determine the influence of the synthesis intracellular nephrogenic MT on the renal handling and functional sensitivity to inorganic Cd and Cd-MT. The isolated perfused rat kidney (IPRK) will be used as the experimental model. The IPRK offers several advantages for studying the renal handling of Cd-MT and the effects of Cd-MT on renal transport and metabolism: perfusate composition can be controlled with respect to transport and metabolic substrates, humoral factors and sulfhydry groups; perfusate concentration of inorganic Cd and Cd-MT can be varied over a wide range without systemic effects; perfusion conditions can be adjusted to facilitate simultaneous measurements of renal transport, metabolism and renal tissue accumulation of Cd or Cd-MT. The proposed study is the first attempt to use th IPRK to investigate the renal toxicoloty of Cd and will establish basic methodology for this potentially valuable technique for studying the renal toxicology of Cd and other nephrotoxic heavy metals.